Intranasal pharmaceutical dosage forms comprising naloxone

ABSTRACT

The present invention relates to an intranasal pharmaceutical dosage form comprising a dosing unit comprising naloxone or a pharmaceutically acceptable salt thereof in an amount of equivalent to ≥0.5 mg naloxone HC dissolved in an application fluid of a volume of ≤250 μl. Furthermore, the present invention relates to such an intranasal pharmaceutical dosage form for use in the treatment of opioid overdosing and/or at least one symptom thereof.

FIELD OF THE INVENTION

The present invention relates to an intranasal pharmaceutical dosageform comprising a dosing unit comprising naloxone or a pharmaceuticallyacceptable salt thereof in an amount of equivalent to ≥0.5 mg naloxoneHCl, preferably an amount of equivalent to between about 0.65 mgnaloxone HCl and about 0.8 mg naloxone HCl or between about 1.3 mgnaloxone HCl and about 1.6 mg naloxone HCl, dissolved in an applicationfluid of a volume of ≥250 μC. Preferably, the dosage form is for use inthe treatment of opioid overdosing and/or at least one symptom thereof.

BACKGROUND OF THE INVENTION

The abuse of opioids, in particular the intravenous injection of opioidssuch as heroin by drug addicts is quite often associated with overdosingof the drug which can be due to a loss of opioid tolerance (e.g. whenabusers are imprisoned or following substitution/detoxificationtherapy), wrong estimation of the amount of the drug consumed, a moreconcentrated form of the drug, or the abuser's desire to produce a“high” despite the drug tolerance developed over time. It has beenestimated that the rate for overdosing in addicts is between 19% and 30%(Darke S et al. “The ratio of non-fatal to fatal heroin overdose;Addiction, 2003 August; 98(8): 1169-71). Such overdosing incidents canlead to the death of the addict (so called “fatal overdosing”). Theannual mortality rate of addicts due to heroin overdosing has beenreported to be 0.8% (Hall et al.; “How many dependent heroin users arethere in Australia?” Med J Aust. 2000 Nov. 20; 173(10):528-31 2000). Theratio of non-fatal to fatal overdosing has been estimated to be between23.8 to 1 and 37.5 to 1 (Darke et al, see above). Thus, non-fataloverdosing represents a considerable number of events among drugaddicts, especially in drug addicts who abuse the drug parenterally,i.e. by injection, requiring an adequate instant treatment by emergencyhealth care personnel.

Naloxone, an opioid antagonist, is known to counteract the actions ofopioids and is used in opioid overdosing emergency cases and in rapidopiate detoxification.

Since the onset of action of naloxone used in such cases should be asfast as possible, naloxone is thus far mainly administered intravenouslyor intramuscularly by emergency health care personnel to the subjectwith an overdosing.

Due to a high first pass metabolism, oral dosage forms comprisingnaloxone display a low bioavailability and thus seem to be not suitablefor such purposes.

The administration of naloxone via injection into the blood stream orinto the muscle requires first of all trained medical personnel (forintravenous injection) or a trained career (for intramuscularinjection). Secondly, depending on the constitution of the addict andthe period of intravenous drug abuse, it can be particularly difficultto find access into a vein of the addict's body for administeringnaloxone intravenously.

Clearly, there is a risk of exposure to blood borne pathogens for themedical personnel or the trained career since a large population of drugaddicts suffers from blood borne pathogen induced diseases such as HIV,hepatitis B and C, and the like since accidental needlestick is aserious safety concern. 385,000 needle-stick injuries have beenestimated to occur in the year 2000 in the US only (Wilburn,“Needlestick and sharps injury prevention, Online J Issues Nurs 2004Sep. 30; 9(3):5).

Furthermore, due to the relatively short elimination half life ofnaloxone administered intravenously, there is the need to re-administernaloxone, in some cases even several times, via this route.

There have been studies on the intranasal administration of naloxone inorder to treat addicts with overdosing. However, their outcome is rathercontroversial. Thus, Loimer et al. reported that the nasaladministration of naloxone is as effective as the intravenous route inopiate addicts (see Loimer N. et al, “Nasal administration of naloxoneis as effective as the intravenous route in opiate addicts”; theInternational Journal of Addictions, 29(6), 819-827, 1994). Dowling etal., on the other hand, reported that naloxone administered intranasallydisplays a relative bioavailability of 4% only and concluded that theintranasal absorption is rapid but does not maintain measurableconcentrations for more than an hour (Dowling et al., “Populationpharmacokinetics of intravenous, intramuscular, and intranasal naloxonein human volunteers”, Ther Drug Monit, Vol 30, No 4, August 2008).

Thus, there is a general need for a naloxone dosage form which caneasily be administered to drug addicts suffering from overdosing bymedically untrained subjects, e.g. by family members or other careers.

Furthermore, even if administered by health care personnel, such dosageform should i) minimize the danger of being exposed to blood bornepathogens and ii) reduce administration time as there is no need foridentifying injectable veins or undressing the subject for intramuscularinjection. Also, such dosage forms should display a fast onset of actionand ideally maintain a counteracting effect over a period of severalhours.

OBJECTS AND SUMMARY OF THE INVENTION

It is thus one objective of the present invention to provide apharmaceutical dosage form comprising naloxone which exhibits aconsiderably high bioavailability of naloxone combined with a fast onsetof action and a relatively long period of action.

It is another objective of the present invention to provide such adosage form for use in the treatment of opioid overdosing and/or atleast one symptom thereof.

Still another object of the present invention resides in the use ofnaloxone or a pharmaceutically acceptable salt thereof in a specificamount dissolved in a specific volume for a dosing unit of such a dosageform.

These and other objects as they will become apparent from the ensuingdescription are attained by the subject matter of the independentclaims. The dependent claims relate to some of the preferred embodimentsof the present invention.

Thus, the present invention is in one aspect concerned with anintranasal pharmaceutical dosage form comprising a dosing unitcomprising naloxone or a pharmaceutically acceptable salt thereof in anamount of equivalent to ≥0.5 mg naloxone HCl dissolved in an applicationfluid of a volume of ≤250 μl.

In a preferred embodiment, the amount of naloxone or a pharmaceuticallyacceptable salt thereof is equivalent to ≥0.6 mg.

In another preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to between about0.65 mg naloxone HCl and about 0.8 mg naloxone HCl or between about 1.3mg naloxone HCl and about 1.6 mg naloxone HCl.

In a particularly preferred embodiment, the present invention relates toan intranasal pharmaceutical dosage form comprising naloxone or apharmaceutically acceptable salt thereof dissolved in an applicationfluid, wherein an amount of equivalent to between about 1.3 mg naloxoneHCl and about 1.6 mg naloxone HCl is administered intranasally, whereinsaid amount is provided by administration to one nostril or wherein saidamount is provided by administration to two nostrils, and wherein thevolume of the application fluid per nostril is ≥250 μl.

In a further preferred embodiment, the volume of the application fluidis ≤200 μl.

In a particularly preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is within a range of equivalentto 0.6 mg naloxone HCl to 12 mg naloxone HCl, preferably equivalent to0.6 mg naloxone HCl to 6 mg naloxone HCl, more preferably equivalent to0.6 mg naloxone HCl to 3.75 mg naloxone HCl, and most preferablyequivalent to 0.6 mg naloxone HCl to 2.0 mg naloxone HCl. Said range canalso be within a range of equivalent to 0.5 mg naloxone HCl to 20 mgnaloxone HCl, or within a range of equivalent to 0.5 mg naloxone HCl to15 mg naloxone HCl, or within a range of equivalent to 0.5 mg naloxoneHCl to 10 mg naloxone HCl. Most preferred is a range of equivalent tobetween about 0.65 mg naloxone HCl and about 0.8 mg naloxone HCl orbetween about 1.3 mg naloxone HCl and about 1.6 mg naloxone HCl.

In another preferred embodiment, an amount of naloxone or apharmaceutically acceptable salt thereof equivalent to about 1.3 mgnaloxone HCl or about 1.4 mg naloxone HCl or about 1.5 mg naloxone HClor about 1.6 mg naloxone HCl is administered intranasally, wherein saidamount is provided by administration to one nostril or wherein saidamount is provided by administration to two nostrils, and wherein thevolume of the application fluid per nostril is ≥250 μl.

In still another preferred embodiment, the volume of the applicationfluid is within a range of 200 μl to 35 μl, preferably of 200 μl to 50μl, more preferably of 200 μl to 100 μl, and most preferably of 150 μlto 100 μl. Said range may also be a range of 250 μl to 35 μl, or 250 μlto 75 μl, or 200 μl to 75 μl. Particularly preferred is a volume of 200μl, or 150 μl, or 100 μl, or 50 μl. For some cases, a volume of 75 μlmay also be used.

In yet another preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 0.6 mgnaloxone HCl, or 0.7 mg naloxone HCl, or 0.8 mg naloxone HCl, or 1.2 mgnaloxone HCl, or 1.4 mg naloxone HCl, or 1.6 mg naloxone HCl, and thevolume of the application fluid is within a range of 200 μl to 50 μl,preferably of 200 μl to 100 μl, and more preferably of 150 μl to 100 μl.It can also be preferred that the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 0.9 mgnaloxone HCl, or 1.0 mg naloxone HCl, or 1.1 mg naloxone HCl, or 1.8 mgnaloxone HCl, or 2.0 mg naloxone HCl, or 2.2 mg naloxone HCl wherein thevolume ranges above are applicable.

In still another preferred embodiment, the final concentration of thenaloxone or a pharmaceutically acceptable salt thereof in theapplication fluid is within a range of equivalent to 3 mg naloxone HClper ml application fluid to 100 mg naloxone HCl per ml applicationfluid, preferably within a range of equivalent to 3 mg naloxone HCl perml application fluid to 70 mg naloxone HCl per ml application fluid, andmore preferably within a range of equivalent to 3 mg naloxone HCl per mlapplication fluid to 24 mg naloxone HCl per ml application fluid.

Preferably, the dosing unit of the intranasal dosage form as claimedherein is administered to a single nostril. Thus, preferably, the abovementioned amount of naloxone or a pharmaceutically acceptable saltthereof is provided by administration to one nostril.

Due to the presence of two nostrils, one application step as definedbelow may be comprised of the consecutive administration of two dosingunits, each to one of the two nostrils. The following preferredembodiments relate to such an application step, i.e. the consecutiveadministration to the two nostrils. Most preferably, such an applicationstep via the consecutive administration to two nostrils results in theintranasal administration of a naloxone amount of equivalent to betweenabout 1.3 mg naloxone HCl and about 1.6 mg naloxone HCl.

In a particularly preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is within a range of equivalentto 0.6 mg naloxone HCl to 6 mg naloxone HCl, preferably equivalent to0.6 mg naloxone HCl to 3 mg naloxone HCl, more preferably equivalent to0.6 mg naloxone HCl to 1.8 mg naloxone HCl, and most preferablyequivalent to 0.6 mg naloxone HCl to 1.0 mg naloxone HCl. Said range canalso be within a range of equivalent to 0.5 mg naloxone HCl to 10 mgnaloxone HCl, or within a range of equivalent to 0.5 mg naloxone HCl to7.5 mg naloxone HCl, or within a range of equivalent to 0.5 mg naloxoneHCl to 5 mg naloxone HCl.

In still another preferred embodiment, the volume of the applicationfluid is within a range of 200 μl to 35 μl, preferably of 200 μl to 50μl, more preferably of 200 μl to 100 μl, and most preferably of 150 μlto 100 μl. Said range may also be a range of 250 μl to 35 μl, or 250 μlto 75 μl, or 200 μl to 75 μl. Particularly preferred is a volume of 200μl, or 150 μl, or 100 μl. For some cases, a volume of 75 μl may also beused.

In yet another preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 0.6 mgnaloxone HCl or 0.7 mg naloxone HCl or 0.8 mg naloxone HCl, and thevolume of the application fluid is within a range of 200 μl to 50 μl,preferably of 200 μl to 100 μl, and more preferably of 150 μl to 100 μl.It can also be preferred that the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 0.9 mgnaloxone HCl, or 1.0 mg naloxone HCl, or 1.1 mg naloxone HCl, whereinthe volume ranges above are applicable.

In still another preferred embodiment, the final concentration of thenaloxone or a pharmaceutically acceptable salt thereof in theapplication fluid is within a range of equivalent to 3 mg naloxone HClper ml application fluid to 100 mg naloxone HCl per ml applicationfluid, preferably within a range of equivalent to 3 mg naloxone HCl perml application fluid to 70 mg naloxone HCl per ml application fluid, andmore preferably within a range of equivalent to 3 mg naloxone HCl per mlapplication fluid to 12 mg naloxone HCl per ml application fluid.

Due to the presence of two nostrils, one application step as definedbelow may also be comprised of a single administration to one of the twonostrils only. The following preferred embodiments relate to such anapplication step, i.e. the single administration to one nostril only.Most preferably, such an application step to one nostril only results inthe intranasal administration of a naloxone amount of equivalent tobetween about 1.3 mg naloxone HCl and about 1.6 mg naloxone HCl.

In a particularly preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is within a range of equivalentto 1.2 mg naloxone HCl to 12 mg naloxone HCl, preferably equivalent to1.2 mg naloxone HCl to 6 mg naloxone HCl, more preferably equivalent to1.2 mg naloxone HCl to 3.75 mg naloxone HCl, and most preferablyequivalent to 1.2 mg naloxone HCl to 2.0 mg naloxone HCl. Said range canalso be within a range of equivalent to 1.0 mg naloxone HCl to 20 mgnaloxone HCl, or within a range of equivalent to 1.0 mg naloxone HCl to15 mg naloxone HCl, or within a range of equivalent to 1.0 mg naloxoneHCl to 10 mg naloxone HCl.

In still another preferred embodiment, the volume of the applicationfluid is within a range of 200 μl to 35 μl, preferably of 200 μl to 50μl, more preferably of 200 μl to 100 μl, and most preferably of 150 μlto 100 μl. Said range may also be a range of 250 μl to 35 μl, or 250 μlto 75 μl, or 200 μl to 75 μl. Particularly preferred is a volume of 200μl, or 150 μl, or 100 μl. For some cases, a volume of 75 μl may also beused.

In yet another preferred embodiment, the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 1.2 mgnaloxone HCl or 1.4 mg naloxone HCl or 1.6 mg naloxone HCl, and thevolume of the application fluid is within a range of 200 μl to 50 μl,preferably of 200 μl to 100 μl, and more preferably of 150 μl to 100 μl.It can also be preferred that the amount of naloxone or apharmaceutically acceptable salt thereof is equivalent to 1.8 mgnaloxone HCl, or 2.0 mg naloxone HCl, or 2.2 mg naloxone HCl, whereinthe volume ranges above are applicable.

In still another preferred embodiment, the final concentration of thenaloxone or a pharmaceutically acceptable salt thereof in theapplication fluid is within a range of equivalent to 6 mg naloxone HClper ml application fluid to 100 mg naloxone HCl per ml applicationfluid, preferably within a range of equivalent to 6 mg naloxone HCl perml application fluid to 70 mg naloxone HCl per ml application fluid, andmore preferably within a range of equivalent to 6 mg naloxone HCl per mlapplication fluid to 24 mg naloxone HCl per ml application fluid.

In yet another preferred embodiment relating to all embodiments above,the application fluid is selected from the group comprising water, anaqueous solution optionally comprising a pharmaceutical solvent, anaqueous solution comprising a pharmaceutical solvent and co-solvent andan aqueous saline solution. Preferably, the aqueous saline solution is aNaCl solution, more preferably NaCl in purified water at a concentrationof about 1.0% weight/volume, most preferably NaCl in purified water atconcentration of about 0.9% weight/volume. Preferably, the pH-value ofthe application fluid corresponds to a pH≤about 6.0, preferably to apH≤about 5.8, more preferably to a pH≤about 5.6 and most preferably to apH≤about 5.5.

In another preferred embodiment, the dosage form comprises at least twodosage units, preferably at least three dosage units, more preferably atleast four dosage units and most preferably at least five dosage units.The dosage form may also comprise only one dosage unit, or exactly two,three, four, or five dosage units.

Generally, the dosage form may comprise the above mentioned amount orhalf of said amount dissolved in an application fluid in a dosing unit,the amount being dependent on whether said total amount is provided byadministration to one nostril or by administration to two nostrils.Thus, if said amount is administered to one nostril, the dosage formpreferably comprises said total amount dissolved in an application fluidin a dosing unit. If said amount is administered to two nostrils, thedosage form preferably comprises half of said total amount dissolved inan application fluid in a dosing unit.

Preferably, said dosing unit comprises naloxone or a pharmaceuticallyacceptable salt thereof in an amount of equivalent to between about 0.65mg naloxone HCl and about 0.8 mg naloxone HCl if a single applicationstep comprises the administration to two nostrils. About 0.65 mg, about0.70 mg, about 0.75 mg or about 0.80 mg may be particularly preferred.

Preferably, said dosing unit comprises naloxone or a pharmaceuticallyacceptable salt thereof in an amount of equivalent to between about 1.3mg naloxone HCl and about 1.6 mg naloxone HCl if a single applicationstep comprises the administration to one nostril. About 1.30 mg, about1.35 mg, about 1.40 mg, about 1.45 mg, about 1.50 mg, about 1.55 mg orabout 1.60 mg may be particularly preferred.

A dosage form may comprise a single dosing unit only and may thus be forsingle use if said amount is administered to one nostril. If said amountis administered to two nostrils, the dosage form may comprise two dosingunits and may still be for single use. However, said dosage form mayalso comprise at least two dosing units, preferably at least threedosing units, more preferably at least four dosing units and mostpreferably at least five dosing units and may thus be for multiple uses.

In still another preferred embodiment, the dosage form is selected fromthe group of dosage forms comprising a nasal spray (which may also bereferred to as spraying device), a nasal mucoadhesive dosage form and aMucosal Atomizer Device. A nasal spray may be particularly preferred forthe present invention. Said nasal spray may particularly be asyringe-driven spraying device or a pump-driven spraying device.

Preferably, the dosage form comprises naloxone as the onlypharmaceutically active agent. Thus, no further pharmaceutically activeagent(s) such as e.g. epinephrine may be comprised in the dosage form.

In yet another preferred embodiment, the dosage form provides for a highbioavailability of the active agent naloxone in humans, preferably for abioavailability of about 20% to about 40%, more preferably of about 25%to about 35%, as determined against a reference of intravenouslyadministration naloxone with a bioavailability set to 100%.

In still another preferred embodiment, the dosage form provides for afast onset of action of the active agent naloxone in humans, i.e. a lowtmax, preferably a fast onset of action within about 5 minutes to about18 minutes upon administration, preferably within about 5 minutes toabout 12 minutes upon administration, more preferably within about 5minutes to about 10 minutes upon administration and most preferablywithin about 6 minutes upon administration.

In yet another preferred embodiment, the dosage form provides for a longplasma half-live of the active agent naloxone in humans, i.e. a slowelimination pattern, preferably a plasma half-live of about 1.5 hours toabout 9 hours upon administration, more preferably a plasma half-live ofabout 2.5 hours to about 9 hours upon administration and most preferablya plasma half-live of about 4 hours to about 9 hours uponadministration. The plasma half-live of the active agent naloxone inhumans can also be about 1 hour, about 1.5 hours, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours or about 9 hours upon administration of the dosage formaccording to the present invention.

In a second aspect, the present invention is concerned with thetreatment of opioid overdosing and/or at least one symptom thereof.

Thus, in said aspect, the above mentioned dosage form including allpreferred embodiments mentioned above is for use in the treatment ofopioid overdosing and/or at least one symptom thereof.

In a particularly preferred embodiment, the present invention relates toan intranasal pharmaceutical dosage form comprising naloxone or apharmaceutically acceptable salt thereof dissolved in an applicationfluid for use in the treatment of opioid overdosing and/or at least onesymptom thereof, wherein an amount of equivalent to between about 1.3 mgnaloxone HCl and about 1.6 mg naloxone HCl is administered intranasally,wherein said amount is provided by administration to one nostril orwherein said amount is provided by administration to two nostrils, andwherein the volume of the application fluid per nostril is 5 about 250μl, preferably 5 about 200 μl.

The present invention therefore also relates to a method of treatingopioid overdosing and/or at least one symptom thereof, wherein naloxoneor a pharmaceutically acceptable salt thereof is administeredintranasally in an amount of equivalent to ≥0.5 mg naloxone HCl in anapplication of a volume of s 250 μl.

The opioid overdosing may be due to the misuse of heroin, buprenorphine,methadone, fentanyl, oxycodone, morphine and hydromorphone. Thus, theopioid overdosing may be caused by the illicit use of opioids. However,the opioid overdosing may also be caused by an accidental misuse ofopioids during opioid therapy.

In a preferred embodiment, the opioid overdosing symptom is selectedfrom the group comprising respiratory depression, optionallypostoperative opioid respiratory depression, altered levelconsciousness, miotic pupils, hypoxemia, acute lung injury andaspiration pneumonia.

In a further preferred embodiment, the dosage form is re-applied duringan initial titration period in order to provide for an effective amountof naloxone. The above mentioned amount may thus be re-administeredduring an initial titration period in order to provide for an effectiveamount of naloxone when used for treating an opioid overdosing and/or atleast one symptom thereof. Preferably, said initial titration period isa period of about 15 to about 30 minutes starting with the firstapplication step. It can be preferred to re-apply the dosage formaccording to the present invention two times, three times, four times,five times or even six times in order to provide for an amount ofnaloxone effective in treating opioid overdosing and/or at least onesymptom thereof.

In another preferred embodiment, the dosage form according to thepresent invention is combined with an intramuscular and/or intravenousdosage form comprising naloxone or a pharmaceutically acceptable saltthereof. It can be preferred that said intramuscular and/or intravenousdosage form comprises naloxone or a pharmaceutically acceptable saltthereof in amounts ranging from about 0.4 mg to about 2 mg.

The present invention is also concerned in one aspect with the use ofnaloxone or a pharmaceutically acceptable salt thereof in an amount ofequivalent to ≥1.0 mg naloxone HCl, preferably of between about 0.65 mgnaloxone HCl and about 0.8 mg naloxone HCl or between about 1.3 mgnaloxone HCl and about 1.6 mg naloxone HCl, dissolved in an applicationfluid of a volume of ≤250 μl in a dosing unit of an intranasalpharmaceutical dosage form.

In preferred embodiments, all the amounts of naloxone and volumes of theapplication fluid as mentioned above can be used in a dosing unit of anintranasal pharmaceutical dosage form.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the phases of the study described in Example 1, with:

SD: study drug according to random sequence code

P1-P4: Periods 1-4 each identical with a single dose of study drugaccording to random sequence code, followed by a ≥14 day washout(Periods 1, 2 and 3 only).

FIG. 2 shows the pharmacokinetic parameters of the study described inExample 1.

FIG. 3 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV), 1.2 mg naloxone applied intranasally (IN)and 1.6 mg naloxone applied IN for a period of 36 hours.

FIG. 4 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV), 1.2 mg naloxone applied intranasally (IN)and 1.6 mg naloxone applied IN for a period of 4 hours.

FIG. 5 shows the estimated curves (based on the data of Example 1: 16 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV), 1.2 mg naloxone applied intranasally (IN)and 1.6 mg naloxone applied IN for a period of 36 hours.

FIG. 6 shows the estimated curves (based on the data of Example 1: 16 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV), 1.2 mg naloxone applied intranasally (IN)and 1.6 mg naloxone applied IN for a period of 4 hours.

FIG. 7 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using either Excel or WinNonlin for0.4 mg naloxone applied intravenously (IV, Excel only), 1.2 mg naloxoneapplied intranasally (IN) and 1.6 mg naloxone applied IN for a period of4 hours.

FIG. 8 shows the estimated curves (based on the data of Example 1: 16 mgnaloxone HCl applied intranasally) using either Excel or WinNonlin for0.4 mg naloxone applied intravenously (IV, Excel only), 1.2 mg naloxoneapplied intranasally (IN) and 1.6 mg naloxone applied IN for a period of4 hours.

FIG. 9 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV) [wherein, compared to FIG. 3, one outlyingsubject was excluded], 1.2 mg naloxone applied intranasally (IN) and 1.6mg naloxone applied IN for a period of 36 hours.

FIG. 10 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV) [wherein, compared to FIG. 4, one outlyingsubject was excluded], 1.2 mg naloxone applied intranasally (IN) and 1.6mg naloxone applied IN for a period of 4 hours.

FIG. 11 shows the estimated curves (based on the data of Example 1: 16mg naloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV) [wherein, compared to FIG. 5, one outlyingsubject was excluded], 1.2 mg naloxone applied intranasally (IN) and 1.6mg naloxone applied IN for a period of 36 hours.

FIG. 12 shows the estimated curves (based on the data of Example 1: 16mg naloxone HCl applied intranasally) using Excel for 0.4 mg naloxoneapplied intravenously (IV) [wherein, compared to FIG. 6, one outlyingsubject was excluded], 1.2 mg naloxone applied intranasally (IN) and 1.6mg naloxone applied IN for a period of 4 hours.

FIG. 13 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using WinNonlin for 1.2 mg naloxoneapplied intranasally (IN) and 1.6 mg naloxone applied IN as well as for0.4 mg naloxone applied intravenously (IV, using Excel [wherein,compared to FIG. 7, one outlying subject was excluded]) for a period of4 hours.

FIG. 14 shows the estimated curves (based on the data of Example 1: 16mg naloxone HCl applied intranasally) using WinNonlin for 1.2 mgnaloxone applied intranasally (IN) and 1.6 mg naloxone applied IN aswell as for 0.4 mg naloxone applied intravenously (IV, using Excel[wherein, compared to FIG. 8, one outlying subject was excluded]) for aperiod of 4 hours.

FIG. 15 shows the estimated curves (based on the data of Example 1: 8 mgnaloxone HCl applied intranasally) using either Excel or WinNonlin for1.2 mg naloxone applied intranasally (IN) and 1.6 mg naloxone applied INfor a period of 4 hours as well as for 0.4 mg naloxone appliedintravenously (IV, using Excel [wherein, compared to FIG. 7, oneoutlying subject was excluded]).

FIG. 16 shows the estimated curves (based on the data of Example 1: 16mg naloxone HCl applied intranasally) using either Excel or WinNonlinfor 1.2 mg naloxone applied intranasally (IN) and 1.6 mg naloxoneapplied IN for a period of 4 hours as well as for 0.4 mg naloxoneapplied intravenously (IV, using Excel [wherein, compared to FIG. 8, oneoutlying subject was excluded]).

DETAILED DESCRIPTION OF THE INVENTION

The present invention partially resides in the surprising finding thatan intranasal pharmaceutical dosage form comprising naloxone or apharmaceutically acceptable salt thereof dissolved in an applicationfluid of a volume of ≤250 Cl displays a significant bioavailability,fast onset of action and a relatively slow elimination pattern.

For use in opioid overdosing, such an intranasal dosage form may thusinclude in a dosing unit an amount of naloxone effective to counteractthe actions of the opioid, wherein the dosage form is an easy-to-use andsafe dosage form with the pharmacokinetic parameters set out above,namely a significant bioavailability, fast onset of action and arelatively slow elimination pattern.

Before some of the embodiments of the present invention are described inmore detail, the following definitions are introduced.

As used in the specification and the claims, the singular forms of “a”and “an” also include the corresponding plurals unless the contextclearly dictates otherwise.

The terms “about” and “approximately” in the context of the presentinvention denotes an interval of accuracy that a person skilled in theart will understand to still ensure the technical effect of the featurein question. The term typically indicates a deviation from the indicatednumerical value of 10% and preferably ±5%.

It needs to be understood that the term “comprising” is not limiting.For the purposes of the present invention, the term “consisting of” isconsidered to be a preferred embodiment of the term “comprising of”. Ifhereinafter a group is defined to comprise at least a certain number ofembodiments, this is also meant to encompass a group which preferablyconsists of these embodiments only.

“Naloxone” as referred to herein is a commercially available narcoticantagonist, which is indicated for the blockade of exogenouslyadministered opioids. It acts at all opioid receptor sites (μ, κ, andδ). Following oral administration, naloxone is rapidly absorbed (within5-30 minutes) but has a very low oral bioavailability of <3% due to anextensive first-pass-metabolism. In low oral doses, naloxone does notbecome systemically available but acts mainly on local opioid receptorsin the gastrointestinal tract. In cases of opioid overdoses, naloxonereverses the effects of the abused opioids and is thus used in order totreat overdosing.

The term “a pharmaceutically acceptable salt” of naloxone refers e.g. tothe hydrochloride salt, the sulfate salt, the bisulfate salt, thetartrate salt, the nitrate salt, the citrate salt, the bitartrate salt,the phosphate salt, the malate salt, the maleate salt, the hydrobromidesalt, the hydroiodide salt, the fumerate salt, the succinate salt andthe like. Naloxone may also be present as base addition salts such asthe metal salt of alkali metals including lithium, sodium and potassium.A preferred salt is the hydrochloride salt of naloxone.

The term “intranasal dosage form” as used herein is defined as apharmaceutical dosage form which releases the active agent within thenose. Upon release, the active agent is transported subsequently intothe systemic circulation via the nasal mucosa. Typically, a specificdosing unit or metered volume is applied from the intranasal dosage formto one nostril of the nose per administration step. In order to providefor the complete dosing unit or complete metered volume, it may benecessary to carry out at least one priming step of the intranasaldosage form prior to the administration. In case of a nasal spray, thismean for example that the nasal spray is pumped outside the nose for atleast one time until the pump of the spray is completely filled with themetered volume to be applied.

The term “dosing unit” as used herein refers to a specific amount of theactive agent which is administered in a single administration step to asingle nostril. As set out below, such an amount may be e.g. 0.6 mgnaloxone HCl per nostril in the initial step of treating an opioidoverdosing. Preferably, said amount may be equivalent to between about1.3 mg naloxone HCl and about 1.6 mg naloxone HCl in a dosing unit ifthe total amount is provided by administration to one nostril only in asingle application step. Alternatively, said amount may be equivalent tobetween about 0.65 mg naloxone HCl and about 0.8 mg naloxone HCl in adosing unit if the total amount is provided by administration to twonostrils in a single application step. Since the naloxone orpharmaceutically acceptable salt thereof is dissolved in an applicationfluid to a specific final concentration, the amount administered persingle administration step corresponds to a specific volume to beadministered. In the present invention, said volume is preferably ≤200μl.

The intranasal dosage form of the present invention may e.g. be a nasalspray. It is clear to the skilled person that a nasal spray will in mostcases not only comprise a final volume of ≤200 μl. Rather, said nasalspray may e.g. comprise 1.5 ml, wherein a volume of e.g. 100 μl isadministered per administration step, i.e. as metered volume perapplication. As set out above, priming of the spray may be necessaryprior to the application.

The skilled person is aware that due to the presence of two nostrils,intranasal dosage forms may be administered in a dosage regimen dividedinto two consecutive steps, namely a first administration step of halfof the amount of the active agent to be administered into one nostril,followed by the administration of the other half into the other nostril.This “divided” way of administration is preferred for the presentinvention since smaller volumes per nostril may be used.

In a particularly preferred embodiment, the present invention thusrelates to an intranasal pharmaceutical dosage form comprising naloxoneor a pharmaceutically acceptable salt thereof, wherein an amount ofequivalent to between about 1.3 mg naloxone HCl and about 1.6 mgnaloxone HCl is administered intranasally, wherein said amount isprovided by administration to two nostrils, and wherein the volume ofthe application fluid per nostril is ≥250 μl. An amount of equivalent tobetween about 0.65 mg naloxone HCl and about 0.8 mg naloxone HCl maythus be administered per nostril, arriving at the above total amount.

However, one may also administer the active agent in a singleadministration step into one nostril. Using an identical volume pernostril as for the divided administration to two nostrils, it is obviousfor the skilled person that the concentration of the active agent in theadministration fluid then needs to be twice the concentration in orderto provide for the same amount of the active agent.

In another particularly preferred embodiment, the present invention thusrelates to an intranasal pharmaceutical dosage form comprising naloxoneor a pharmaceutically acceptable salt thereof, wherein an amount ofequivalent to between 1.3 mg naloxone HCl and about 1.6 mg naloxone HClis administered intranasally, wherein said amount is provided byadministration to one nostril, and wherein the volume of the applicationfluid per nostril is ≤250 μl. The amount of equivalent to between 1.3 mgnaloxone HCl and about 1.6 mg naloxone HCl may thus be administered toone nostril only.

Generally, a pharmaceutical dosage form comprises an active agent in aspecific amount in order to achieve a specific effect. Thus, an activeagent may e.g. be comprised in an amount of 10 mg in a tablet, i.e. anoral dosage form. By administering such a tablet in one application stepto a patient, the effective amount of 10 mg is provided in the patient'sbody. As already discussed above, the situation differs for anintranasal administration of an active agent due to the presence of twonostrils. In this respect, it needs to be understood that the finalamount of an active agent administered intranasally is always thetherapeutically active amount, regardless of whether the administrationregimen comprises a single administration step to one nostril only ortwo consecutive administration steps to two nostrils. Both ways, eitherthe single administration step or the two consecutive administrationsteps are referred to herein as “one application step” in the meaning ofproviding the desired therapeutically active amount, e.g. 1.2 mg or anamount of equivalent to between 1.3 mg naloxone HCl and about 1.6 mgnaloxone HCl.

The term “application fluid” as used herein preferably refers to asolution comprising the active agent in a dissolved state. However,“application fluid” as used herein may also refer to a suspensioncomprising at least some of the active agent (and optionally furtheringredients) in a solid phase dispersed throughout a fluid phase. Whenreference to a suspension is made, the term “dissolved” is thus used inthe meaning of “dispersed”. As mentioned below, the formulation used mayalso be a gel or a gel-like formulation. Accordingly, the term“application fluid” also refers to gel or gel-like phases.

The term “bioavailability” as used herein refers to the extent of anactive agent in the systemic circulation and the rate at which an activeagent enters the systemic circulation. The bioavailability of an activeagent with respect to different dosage forms can inter alia be evaluatedby comparing the AUCt-value (see below) provided by a dosage form to beanalyzed (e.g. an intranasal dosage form) with the AUCt-value providedby an intravenous dosage form. Thus, the bioavailability expressed in %may be calculated by dividing the AUCt-value of the dosage form to beanalyzed and the AUCt-value of the intravenous dosage form, andmultiplying by factor 100.

The “Cmax value” indicates the maximum blood plasma concentration of theactive agent naloxone.

The “tmax value” indicates the time point at which the Cmax value isreached. In other words, tmax is the time point of the maximum observedplasma concentration.

The “AUC (Area Under the Curve)” value corresponds to the area under theplasma concentration-time curve. The AUC value is proportional to theamount of the active agent naloxone absorbed into the blood circulationin total and is hence a measure for the bioavailability.

The “AUCt value” is the value for the area under the plasmaconcentration-time curve from the time of administration to the lastmeasurable concentration. AUCt values are usually calculated using thelinear trapezoidal method.

“LambdaZ”, which is the terminal phase rate constant, is estimated usingthose points determined to be in the terminal log-linear phase.

“t½”, also termed “t½z”, which is the apparent terminal phase half-life,is commonly determined from the ratio of ln 2 to LambdaZ.

The areas under the plasma concentration-time curve between the lastmeasured point and infinity may be calculated from the ratio of thefinal observed plasma concentration (Clast) to LambdaZ. This is thenadded to the AUCt to yield “AUCinf”, which is the area under the plasmaconcentration-time curve from the time of administration to infinity.

The inventors have surprisingly found that an intranasal pharmaceuticaldosage form as described herein exhibits upon administration an earlyappearance in the systemic circulation indicated by a low tmax combinedwith relatively long plasma half-life of the naloxone in the systemiccirculation. Moreover, the dosage forms according to the presentinvention also display a reasonably high bioavailability in the range ofbetween about 25% and about 35%.

Without being bound to a scientific theory, the inventors assume atpresent that said remarkable effects of an early tmax and/or arelatively long elimination half-life (i.e. a sustained action ofnaloxone) and/or a rather high bioavailability could be due to rapidabsorption of the whole amount of naloxone at the nasal mucous membranewhich displays a high vascularization. In order to achieve this effect,it appears to be essential to administer the naloxone in a small volumesuch that the loss due to swallowing (which would correspond to oraladministration with a low bioavailability, see above), leaking from thenostrils, and the like is avoided. Therefore, preferably small volumesbelow 0.5 ml of application fluid, more preferably below 0.25 mlapplication fluid should be used for the administration. Generally, thevolumes may be in the range of 30 μl to 400 μl, 35 μl to 350 μl, 40 μlto 300 μl, 50 μl to 250 μl, 60 μl to 200 μl, 70 μl to 150 μl, or 80 μlto 120 μl.

The present invention is to be seen in the background of immediatemedical care in emergency situations, namely in case of opioidoverdosing. In most cases, the overdosing is due to an intravenous abuseof opioids and may result in unconsciousness of the abuser. With thepresent invention at hand, naloxone may be administered in order tocounter the overdosing of the opioid in a safe and efficient way, namelyby intranasal administration.

Moreover, naloxone may be administered by a family member, a friend or acareer of the opioid addict immediately when being confronted with theoverdose situation. Thus, treatment can be initiated even prior to thearrival of emergency health care personnel which clearly reduces therisk of either a fatal outcome of the overdosing or major sequelae dueto the overdosing. In such a scenario, family members, friends or othercareers should thus be provided with an intranasal dosage form accordingto the present invention when living with a subject having potential foran overdosing of opioids.

Since naloxone needs to be present in the systemic circulation of theabuser in a concentration sufficient to counter the effect of theopioid, an effective amount of naloxone has to be provided in oneapplication step. However, depending on the abuser and the severity ofthe overdosing, this effective amount varies and it may thus benecessary to carry out a titration by repeated application steps withina relatively short time until the effective amount is reached.

Typically, the effective amount of naloxone can be determined byassessing the subject's respiratory rate, wherein an increase in therespiratory rate indicates the countering effect of naloxone. If such anincrease should not be detectable upon about 5 to about 10 minutes afteradministration of the first naloxone dose, a second dose should beadministered, followed again by an assessment of the subject'srespiratory rate. If two or several application steps are necessary inorder to reach the effective dose of naloxone, this is typicallyreferred to as “titration”. In the present case, such titration stepsare usually carried out within the first 15 to 20 minutes.

A particularly preferred typical starting amount for an intravenousadministration of naloxone corresponds to about 0.4 mg IV when treatingan opioid overdose and/or a symptom thereof (see also Example 2 of thepresent application). With the present surprising finding (e.g. withrespect to the intranasal bioavailability of naloxone), a most preferredstarting amount of naloxone administered intranasally for use in thetreatment of opioid overdosing and/or at least one symptom thereof thuscorresponds to an amount equivalent to between about 1.3 mg naloxone HCland about 1.6 mg naloxone HCl (wherein said amount is provided byadministration to one nostril or wherein said amount is provided byadministration to two nostrils). Amounts of naloxone equivalent to about1.3 mg naloxone HCl, about 1.4 mg naloxone HCl, about 1.5 mg naloxoneHCl, and about 1.6 mg naloxone HCl may be particularly preferred astypical starting amounts.

Another typical starting point for an effective amount of naloxone maybe an amount of equivalent to about 1.2 mg naloxone HCl administeredintranasally in one application step.

Thus, one may administer a volume of 200 μl application fluid comprisingnaloxone in a concentration of equivalent to 6 mg naloxone HCl per mladministration fluid into a single nostril in order to provide for anamount of 1.2 mg naloxone HCl. Alternatively, a volume of 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 6 mg naloxone HCl per ml administration fluid can be administeredinto the first nostril, followed by the administration of another 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 6 mg naloxone HCl per ml administration fluid into the secondnostril.

Alternatively, one may administer a volume of 150 μl application fluidcomprising naloxone in a concentration of equivalent to 8 mg naloxoneHCl per ml administration fluid into a single nostril in order toprovide for an amount of 1.2 mg naloxone HCl. Alternatively, a volume of75 μl application fluid comprising naloxone in a concentration ofequivalent to 8 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 75 μl application fluid comprising naloxone in a concentrationof equivalent to 8 mg naloxone HCl per ml administration fluid into thesecond nostril.

Still alternatively, one may administer a volume of 100 μl applicationfluid comprising naloxone in a concentration of equivalent to 12 mgnaloxone HCl per ml administration fluid into a single nostril in orderto provide for an amount of 1.2 mg naloxone HCl. Alternatively, a volumeof 50 μl application fluid comprising naloxone in a concentration ofequivalent to 12 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 50 μl application fluid comprising naloxone in a concentrationof equivalent to 12 mg naloxone HCl per ml administration fluid into thesecond nostril.

Another typical starting point for an effective amount may be an amountof equivalent to about 1.6 mg naloxone HCl administered intranasally inone application step.

Thus, one may administer a volume of 200 μl application fluid comprisingnaloxone in a concentration of equivalent to 8 mg naloxone HCl per mladministration fluid into a single nostril in order to provide for anamount of 1.6 mg naloxone HCl. Alternatively, a volume of 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 8 mg naloxone HCl per ml administration fluid can be administeredinto the first nostril, followed by the administration of another 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 8 mg naloxone HCl per ml administration fluid into the secondnostril.

Alternatively, one may administer a volume of 150 μl application fluidcomprising naloxone in a concentration of equivalent to 10.7 mg naloxoneHCl per ml administration fluid into a single nostril in order toprovide for an amount of 1.6 mg naloxone HCl. Alternatively, a volume of75 μl application fluid comprising naloxone in a concentration ofequivalent to 10.7 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 75 μl application fluid comprising naloxone in a concentrationof equivalent to 10.7 mg naloxone HCl per ml administration fluid intothe second nostril.

Still alternatively, one may administer a volume of 100 μl applicationfluid comprising naloxone in a concentration of equivalent to 16 mgnaloxone HCl per ml administration fluid into a single nostril in orderto provide for an amount of 1.6 mg naloxone HCl. Alternatively, a volumeof 50 μl application fluid comprising naloxone in a concentration ofequivalent to 16 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 50 μl application fluid comprising naloxone in a concentrationof equivalent to 16 mg naloxone HCl per ml administration fluid into thesecond nostril.

Still another typical starting point for an effective amount may be anamount of equivalent to about 2.4 mg naloxone HCl administeredintranasally in one application step.

Thus, one may administer a volume of 200 μl application fluid comprisingnaloxone in a concentration of equivalent to 12 mg naloxone HCl per mladministration fluid into a single nostril in order to provide for anamount of 2.4 mg naloxone HCl. Alternatively, a volume of 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 12 mg naloxone HCl per ml administration fluid can be administeredinto the first nostril, followed by the administration of another 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 12 mg naloxone HCl per ml administration fluid into the secondnostril.

Alternatively, one may administer a volume of 150 μl application fluidcomprising naloxone in a concentration of equivalent to 16 mg naloxoneHCl per ml administration fluid into a single nostril in order toprovide for an amount of 2.4 mg naloxone HCl. Alternatively, a volume of75 μl application fluid comprising naloxone in a concentration ofequivalent to 16 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 75 μl application fluid comprising naloxone in a concentrationof equivalent to 16 mg naloxone HCl per ml administration fluid into thesecond nostril.

Still alternatively, one may administer a volume of 100 μl applicationfluid comprising naloxone in a concentration of equivalent to 24 mgnaloxone HCl per ml administration fluid into a single nostril in orderto provide for an amount of 2.4 mg naloxone HCl. Alternatively, a volumeof 50 μl application fluid comprising naloxone in a concentration ofequivalent to 24 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 50 μl application fluid comprising naloxone in a concentrationof equivalent to 24 mg naloxone HCl per ml administration fluid into thesecond nostril.

Yet another typical starting point for an effective amount may be anamount of equivalent to about 3.2 mg naloxone HCl administeredintranasally in one application step.

Thus, one may administer a volume of 200 μl application fluid comprisingnaloxone in a concentration of equivalent to 16 mg naloxone HCl per mladministration fluid into a single nostril in order to provide for anamount of 3.2 mg naloxone HCl. Alternatively, a volume of 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 16 mg naloxone HCl per ml administration fluid can be administeredinto the first nostril, followed by the administration of another 100 μlapplication fluid comprising naloxone in a concentration of equivalentto 16 mg naloxone HCl per ml administration fluid into the secondnostril.

Alternatively, one may administer a volume of 150 μl application fluidcomprising naloxone in a concentration of equivalent to 21.4 mg naloxoneHCl per ml administration fluid into a single nostril in order toprovide for an amount of 3.2 mg naloxone HCl. Alternatively, a volume of75 μl application fluid comprising naloxone in a concentration ofequivalent to 21.4 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 75 μl application fluid comprising naloxone in a concentrationof equivalent to 21.4 mg naloxone HCl per ml administration fluid intothe second nostril.

Still alternatively, one may administer a volume of 100 μl applicationfluid comprising naloxone in a concentration of equivalent to 32 mgnaloxone HCl per ml administration fluid into a single nostril in orderto provide for an amount of 3.2 mg naloxone HCl. Alternatively, a volumeof 50 μl application fluid comprising naloxone in a concentration ofequivalent to 32 mg naloxone HCl per ml administration fluid may beadministered into the first nostril, followed by the administration ofanother 50 μl application fluid comprising naloxone in a concentrationof equivalent to 32 mg naloxone HCl per ml administration fluid into thesecond nostril.

It can also be preferred to start with an amount of equivalent to 4 mgnaloxone HCl, 6 mg naloxone HCl, 8 mg naloxone HCl, 10 mg naloxone HCl,12 mg naloxone HCl, 14 mg naloxone HCl or 16 mg naloxone HCl, whereinsaid amounts are preferably provided in 2×100 μl application fluid fortwo consecutive administrations to two nostrils in one application step.It might be preferred to exclude an amount of equivalent to 1 mg or 2 mgnaloxone HCl administered intranasally as starting point.

It needs to be understood that the above mentioned second administrationstep, i.e. the consecutive administration to the second nostril, is notregarded in the present invention as a repeated administration fortitration purposes. Rather, as outlined above, the administration to thefirst nostril and the administration to the second nostril are regardedas one application step.

It can generally be preferred to administer the naloxone in oneapplication step comprised of two consecutive administration steps, eachcomprising 100 μl application fluid, to the two nostrils. It can furtherbe preferred for such an application step that the concentration ofnaloxone or a pharmaceutically acceptable salt thereof in theapplication fluid is between equivalent to 6 mg naloxone HCl per mlapplication fluid and 80 mg naloxone HCl per ml application fluid,preferably between equivalent to 10 mg naloxone HCl per ml applicationfluid and 70 mg naloxone HCl per ml application fluid, more preferablybetween equivalent to 20 mg naloxone HCl per ml application fluid and 60mg naloxone HCl per ml application fluid, and most preferably betweenequivalent to 20 mg naloxone HCl per ml application fluid and 50 mgnaloxone HCl per ml application fluid. In this setup, a particularlypreferred concentration of naloxone or a pharmaceutically acceptablesalt thereof in the application fluid is between equivalent to 18 mgnaloxone HCl per ml application fluid and 20 mg naloxone HCl per mlapplication fluid Should the starting dose be insufficient as effectivenaloxone dose, another application step may be necessary. In this case,a titration to the effective amount is carried out (see above). Thus, asecond dose may be administered, wherein said second dose preferablycorresponds to the initial first dose administered, i.e. it can beequivalent to 1.2 mg naloxone HCl, 1.6 mg naloxone HCl, 2.4 mg naloxoneHCl or 3.2 mg naloxone HCl. In a preferred embodiment, said second dosemay correspond to an amount equivalent to between about 1.3 mg naloxoneHCl and about 1.6 mg naloxone HCl (wherein said amount is provided byadministration to one nostril or wherein said amount is provided byadministration to two nostrils).

As for the first dose, the administration of the second dose maycomprise a single administration step only, i.e. to one nostril, or maycomprise two consecutive administration steps to two nostrils in orderto provide for the one application step.

In some cases, it may be necessary to apply a third dose or even afourth or fifth dose of naloxone in separate application steps in orderto achieve the desired effect.

It needs to be understood that all the above mentioned application stepsare to be seen as steps carried out during the initial treatment phase,typically within the first about 15 to about 30 minutes. As alreadymentioned above, the inventors have surprisingly found that a slowelimination pattern is achieved by the present invention. Thus, arepeated administration of naloxone may not be necessary.

In some overdosing cases, it may, however, be necessary to re-administernaloxone intranasally or by a different route in order to maintain thecountering effect. Such a re-administration may e.g. be necessary afterabout 2, 3, 4, 5 or 6 hours following the first administration (whereinthe first administration may include several application steps duringthe initial titration).

When re-administering naloxone via the intranasal route, the same dosesand volumes as indicated above may be used. Thus, said re-administrationdose preferably corresponds to the first dose administered.

In another preferred embodiment, at least one of the intranasalpharmaceutical dosage form as described herein is combined with anintramuscular and/or intravenous dosage form comprising naloxone. Thus,the intranasal pharmaceutical dosage form may be administered prior toor subsequent to the administration of the intramuscular and/orintravenous dosage form comprising naloxone. Such a combinedadministration may be necessary depending on the condition of thesubject to be treated and will usually be judged by trained medicalpersonnel. When combining the present intranasal administration with anintramuscular and/or intravenous administration, it can be preferredthat about 0.4 mg to about 2 mg naloxone are administeredintramuscularly and/or intravenously.

As can be deduced from the example section of the present invention, anintranasal dosage form comprising naloxone dissolved in a small volumeprovides for a low tmax, a high bioavailability and a relatively longelimination half-life.

Compared to oral dosage forms comprising naloxone, the bioavailabilityexhibited by the intranasal dosage form of the present invention seemsto be higher by a factor of at least about 10. Also, the tmax seems tobe lower compared to the tmax of an oral dosage form.

Compared to intravenously administered naloxone, wherein thebioavailability is set to 100% (and used as reference), thebioavailability of a dosage form of the present invention seems to bereasonably high. Intravenously administered naloxone displays a fastonset of action within about 1 to 2 minutes, which seems to be onlyslightly faster than the onset of action by a dosage form of the presentinvention.

As confirmed by the study described in the example section of thepresent invention, intravenously administered naloxone exhibits anelimination half life of about 60 to 90 minutes. This rather shortelimination half life of intravenously administered naloxone requires arepeated administration or a continuous infusion in order to avoid therecurrence of the symptoms of opioid overdosing, such as e.g.respiratory depression.

Clearly, this intravenous re-administration or continuous infusion isaccompanied with drawbacks such as the need for qualified medicalpersonnel with the repeated danger of needlestick injury or the need tomonitor a continuous infusion by such personnel. This may be overcome bythe dosage form of the present invention since the intranasal dosageforms of the present invention display an elimination half life of aboutseveral hours.

Thus the pharmaceutical dosage forms of the present invention seem to beparticularly suitable in order to be administered in case of an opioidoverdosing in order to reverse the overdosing and/or the symptomsthereof, such as e.g. respiratory depression.

Preferably, the intranasal dosage form is a nasal spray, a nasalmucoadhesive dosage form or a Mucosal Atomizer Device, all of which caneasily be administered not only by trained medical personnel but also bya medically untrained subject. For the present indication, it ispreferred that the intranasal dosage form corresponds to a devicecapable of functioning in a supine position as well as in uprightposition; such devices are clearly preferred in the present invention(see also device referred to above).

The formulation which is used in the intranasal dosage form may be asolution, a suspension or a nasal gel/gel-like formulation. Gel orgel-like formulations may particularly be used if additional sustainedrelease of naloxone is aimed at.

Typical pharmaceutical excipients used in intranasal formulations areknown to the skilled person and can be used for the formulationsaccording to the present invention. This includesabsorption/permeability enhancer as well as binders, carriers and thelike which are known to the skilled person. The skilled person isfurther aware that other typical reagents such as a tonicity agent, abuffer, a solvent, a co-solvent, a viscosity agent or a gelling agentmay be use in the formulation.

Particularly preferred is the use of a nasal spray. Thus, one may e.g.use a nasal spray comprising a dosing unit comprising naloxone or apharmaceutically acceptable salt thereof in an amount of equivalent to≥0.6 mg naloxone HCl dissolved in an application fluid of a volume≥200μl. Particularly preferred can be the use of 0.6 mg naloxone HCl in anapplication fluid of a volume of 100 μl per dosing unit of the nasalspray. One application step comprising two consecutive administrationsto the two nostrils would thus result in the provision of an amount of1.2 mg naloxone HCl. Most preferred is an amount of equivalent tobetween about 0.65 mg naloxone HCl and 0.8 mg naloxone HCl or betweenabout 1.3 mg naloxone HCl and about 1.6 mg naloxone HCl.

Alternatively, one may use 0.8 mg naloxone HCl in an application fluidof a volume of 100 μl per dosing unit of the nasal spray. Oneapplication step comprising two consecutive administrations to the twonostrils would thus result in the provision of an amount of 1.6 mgnaloxone HCl. The nasal spray may in total comprise at least 600 μlwhich appears to be sufficient for at least five dosage units andresidual volume needed e.g. for priming. Clearly, re-application for aninitial titration or for application at later stages should be possibleusing such a spray.

Generally, the following volumes per dosing unit may particularly beused in the nasal spray according to the present invention: about 25 μl,about 50 μl, about 70 μl, about 90 μl, about 100 μl, about 120 μl, about130 μl or about 140 μl.

Parameters describing the blood plasma curve can be obtained in clinicaltrials, first by once-off intranasal administration of the active agentnaloxone to a number of test persons. The blood plasma values of theindividual test persons are then averaged, e.g. a mean AUC, Cmax andtmax value is obtained. In the context of the present invention,pharmacokinetic parameters such as AUC, Cmax and tmax refer to meanvalues. Further, in the context of the present invention, in vivoparameters such as values for AUC, Cmax, tmax, refer to parameters orvalues obtained after administration of a single dose to human patientsand/or healthy human subjects.

If pharmacokinetic parameters such as mean tmax, Cmax and AUC aremeasured for healthy human subjects, they are typically obtained bymeasuring the development of blood plasma values over time in a testpopulation of approximately 10 to 25 healthy human subjects. Regulatorybodies such as the European Agency for the Evaluation of MedicinalProducts (EMEA) or the Food and Drug Administration (FDA) will usuallyaccept data obtained from e.g. 20 or 24 test persons. Preferably theparameters obtained relate to single dose administration studies.

The term “healthy” human subject in this context refers to a typicalmale or female of usually Caucasian origin with average values asregards height, weight and physiological parameters such as bloodpressure etc. Healthy human subjects for the purposes of the presentinvention are selected according to inclusion and exclusion criteriawhich are based on and in accordance with recommendations of theInternational Conference for Harmonization of Clinical Trials (ICH). Forthe purposes of the present invention, healthy subjects may beidentified according to the inclusion and exclusion criteria as outlinedin the example section.

Further preferred embodiments of the present invention relate to:

-   -   1. An intranasal pharmaceutical dosage form comprising naloxone        or a pharmaceutically acceptable salt thereof dissolved in an        application fluid to a final concentration of between equivalent        to 5 mg naloxone HCl per ml application fluid and 100 mg        naloxone HCl per ml application fluid, preferably of between        equivalent to 5 mg naloxone HCl per ml application fluid and 70        mg naloxone HCl per ml application fluid.    -   2. Dosage form according to 1, wherein a volume of between 200        μl and 50 μl of the application fluid, preferably a volume of        200 μl application fluid, more preferably a volume of 100 μl        application fluid is administered per nostril.    -   3. Dosage form according to 1, wherein said final concentration        is between equivalent to 6.5 mg naloxone HCl per ml application        fluid and 33 mg naloxone HCl per ml application fluid.    -   4. Dosage form according to 3, wherein a volume of 200 μl        application fluid, preferably of 100 μl application fluid, is        administered per nostril.    -   5. Dosage form according to 1, wherein said final concentration        is between equivalent to 8.5 mg naloxone HCl per ml application        fluid and 44 mg naloxone HCl per ml application fluid.    -   6. Dosage form according to 5, wherein a volume of 150 μl        application, preferably of 75 μl application fluid, is        administered per nostril.    -   7. Dosage form according to 1, wherein said final concentration        is between equivalent to 13 mg naloxone HCl per ml application        fluid and 66 mg naloxone HCl per ml application fluid.    -   8. Dosage form according to 7, wherein a volume of 100 μl        application fluid, preferably of 50 μl application fluid, is        administered per nostril.    -   9. Dosage form according to 1, wherein said final concentration        is between equivalent to 18.5 mg naloxone HCl per ml application        fluid and 94 mg naloxone HCl per ml application fluid.    -   10. Dosage form according to 9, wherein a volume of 70 μl        application fluid, preferably of 35 μl application fluid, is        administered per nostril.    -   11. Dosage form according to any of 1 to 10, wherein said dosage        form is for use in the treatment of opioid overdosing and/or at        least one symptom thereof.

Still further preferred embodiments of the present invention relate to:

-   -   1. An intranasal pharmaceutical dosage form comprising a dosing        unit comprising naloxone or a pharmaceutically acceptable salt        thereof in an amount of equivalent to ≥0.5 mg naloxone HCl,        preferably equivalent to ≥0.6 mg naloxone HCl, dissolved in an        application fluid of a volume of ≤250 μl, preferably of a volume        of ≥200 μl.    -   2. Dosage form according to 1, wherein the amount of naloxone or        a pharmaceutically acceptable salt thereof is within a range of        equivalent to 0.6 mg naloxone HCl to 12 mg naloxone HCl,        preferably equivalent to 0.6 mg naloxone HCl to 6 mg naloxone        HCl, more preferably equivalent to 0.6 mg naloxone HCl to 3.75        mg naloxone HCl, and most preferably equivalent to 0.6 mg        naloxone HCl to 2.0 mg naloxone HCl.    -   3. Dosage form according to 1 or 2, wherein the volume of the        application fluid is within a range of 200 μl to 35 μl,        preferably of 200 μl to 50 μl, more preferably of 200 μl to 100        μl, and most preferably of 150 μl to 100 μl.    -   4. Dosage form according to any of 1 to 3, wherein the amount of        naloxone or a pharmaceutically acceptable salt thereof is        equivalent to 0.6 mg naloxone HCl or 1.2 mg naloxone HCl, and        the volume of the application fluid is within a range of 200 μl        to 50 μl, preferably of 200 μl to 100 μl, and more preferably of        150 μl to 100 μl.    -   5. Dosage form according to any of 1 to 4, wherein the dosage        form provides for a bioavailability of the active agent naloxone        in humans of 20% to 40% as determined against a reference of        intravenously administered naloxone with a bioavailability set        to 100%.    -   6. Dosage form according to any of 1 to 5, wherein the dosage        form provides for an onset of action of the active agent        naloxone in humans within 5 minutes to 18 minutes upon        administration.    -   7. Dosage form according to any of 1 to 6, wherein the dosage        form provides for a plasma half-live of the active agent        naloxone in humans of 1.5 hours to 9 hours upon administration.    -   8. Dosage form according to any of 1 to 7, wherein the        application fluid is selected from the group comprising water        and an aqueous saline solution, preferably NaCl in water, more        preferably NaCl in water to a concentration of 0.9%        weight/volume.    -   9. Dosage form according to any of 1 to 8, wherein the dosage        form comprises at least two dosage units, preferably at least        three dosage units, more preferably at least four dosage units        and most preferably at least five dosage units.    -   10. Dosage form according to any of 1 to 9, wherein the dosage        form is selected from the group of dosage forms comprising a        nasal spray, a nasal mucoadhesive dosage form and a Mucosal        Atomizer Device.    -   11. Dosage form according to any of 1 to 10, wherein said dosage        form is for use in the treatment of opioid overdosing and/or at        least one symptom thereof.    -   12. Dosage form according to 12, wherein the opioid overdosing        symptom is selected from the group comprising respiratory        depression, altered level consciousness, miotic pupils,        hypoxemia, acute lung injury and aspiration pneumonia.    -   13. Dosage form according to 11 or 12, wherein the dosage form        is re-applied during an initial titration period in order to        provide for an effective amount of naloxone.    -   14. Dosage form according to any one of 11 to 13, wherein the        dosage form is combined with an intramuscular and/or intravenous        dosage form comprising naloxone or a pharmaceutically acceptable        salt thereof.    -   15. Use of naloxone or a pharmaceutically acceptable salt        thereof in an amount of equivalent to ≥0.5 mg naloxone HCl        dissolved in an application fluid of a volume of ≥250 μl in a        dosing unit of an intranasal pharmaceutical dosage form.

EXAMPLES

Examples of embodiments of the present invention are outlined below.However, the examples should not be construed as limiting the scope ofthe present invention.

Example 1

In the following, the results of a single-center, open-label, randomizedinvestigation in healthy volunteers to determine the intranasal andsublingual bioavailabilities of naloxone in a four-way crossover studyare set out.

Summary of the Study

Objectives:

To assess the absolute bioavailability of 8 mg and 16 mg intranasallyand 16 mg sublingually administered naloxone compared with 1 mg ofintravenously administered naloxone to healthy subjects.

Methodology:

A single-center, open-label, randomized, 4-way crossover study using 8mg and 16 mg intranasally, 16 mg naloxone sublingually, and 1 mgintravenous naloxone. A 4-sequence Williams design was used.

Number of Subjects:

Planned: 12 subjects; full analysis for PK metrics: 12 subjects; Safetypopulation: 12 subjects; Completed: 10 subjects; Discontinued: 2subjects [due to their own choice].

Indication and Criteria for Inclusion:

Subjects were males and/or females aged ≥18 and ≤55 years who were ingood health as determined by no clinically significant findings inmedical history, physical examination (including nasopharyngeal and oralcavity), electrocardiograms (ECGs), and clinical laboratorydeterminations.

Test Treatment, Dose, and Mode of Administration:

1. Naloxone 8 mg and 16 mg were administered as 400 μl intranasally (200μl per nostril). This corresponded to approximately 0.11 mg/kgbodyweight (for 8 mg) and 0.22 mg/kg bodyweight (for 16 mg).

The administration was as follows:

The pump of the nasal spray was primed by removing the cap and pressingdownward. This is repeated at least 6 times or until a fine sprayappears; priming is done just prior to dosing.

The subject is in a standing or upright position and should gently blowthe nose to clear the nostrils. The subject should tilt the head forwardslightly and gently close one nostril by pressing the outside of thenose with a finger on the nostril to be closed.

The device is inserted into the open nostril and it is sprayed 2 timesinto the nostril.

The subject should gently breath inward through the nostril, the deviceis removed, and the steps are repeated for the other nostril.

2: Naloxone 16 mg was administered sublingually in a 1 ml solution whichwas retained under the tongue for 5 minutes.

Naloxone hydrochloride powder was obtained from Mallenckrodt Chemical(Lot no. E09611). Solutions were prepared in 0.9% sodium chloridesolution (pH adjusted to 5.6).

Reference Treatment, Dose, and Mode of Administration:

Intravenous naloxone 1 mg administered as a 1 ml bolus over a 30-secondperiod. Naloxone hydrochloride 1 mg/ml in 10 ml vials was obtained fromBristol-Meyers Squibb Holdings Pharma, Ltd, USA.

Duration of Treatment and Study:

The screening period occurred within 14 days prior to dosing inPeriod 1. There were 4 single-dose, open-label treatments, with aminimum 14-day washout between each treatment. Subjects had anEnd-of-Study medical evaluation after assessments for the fourth dosingwere complete on Day 45, or upon early study discontinuation (see FIG.1).

Treatment Schedule:

Single dose of study drug in each of 4 study periods; each dose of studydrug followed by at least a 14-day washout period (Periods 1, 2 and 3only).

Criteria for Evaluation:

Analysis Populations:

The enrolled population was defined as any subject who signed anInformed Consent Form. The safety population was defined as any subjectwho received any study treatment and had at least one subsequent safetyassessment. The full analysis population for pharmacokinetic metrics wasdefined as those subjects who received a study treatment and had atleast one subsequent valid PK metric.

Pharmacokinetic/Blood Sampling Times:

Blood sampling for pharmacokinetics was performed at the following timesrelative to each dose: time 0 (just prior to dosing), Minutes 1, 2, 4,10, 30, 40 and Hours 1, 2, 4, 6, 8, 12, 16, 24.

Pharmacokinetic Metrics:

Individual subject pharmacokinetic metrics for naloxone and 6β-naloxolAUCt, AUCINF, Cmax, tmax, Lambdaz and t½z were derived usingnoncompartmental methods by a validated pharmacokinetic analysisprogram.

Safety:

Safety was assessed using adverse events, clinical laboratory results,vital signs, and ECGs.

Bioanalytical Methods:

Plasma concentrations of naloxone and 6β-naloxol were quantified byLC-MS/MS methodology using a previously validated assay. Additionally,subject plasma samples were assayed (via GLP and/or non-GLP methods) forother relevant naloxone metabolites.

Statistical Methods:

Plasma concentrations and pharmacokinetic metrics were summarizeddescriptively (n, mean, SD, geometric mean where appropriate for AUCt,AUCINF and Cmax, SE (for concentrations only), median, minimum andmaximum were determined) for each analyte for each treatment. Absolutebioavailabilities of the intranasal and sublingual treatments werecalculated.

Details of the Study

Study Design:

The study was a single-dose, open-label, 4-treatment, 4-period,randomized, crossover study in healthy adult male and female subjects inorder to assess the pharmacokinetics of two doses of nasallyadministered and one dose of sublingually administered naloxone comparedwith intravenously administered naloxone. Subjects received each of the4 treatments according to a random code, with at least a 14-day washoutperiod between each dosing. Subjects were screened within 14 days beforethe first dosing day. Eligible subjects then checked in to the studyunit on the evening before dosing in each study period. Subjects wereadministered the study drug the next morning, following an overnightfast. Pharmacokinetic blood samples were taken for 36 hours afteradministration of study drug in each study period, and subjects weredischarged after the 24-hour blood sample. Subjects returned to thestudy unit to provide the 36-hr PK blood sample. Throughout the study,vital signs were monitored and adverse events (AEs) recorded. Subjectsunderwent end-of-study procedures, similar to those at screening, duringtheir final outpatient visit or upon early termination/discontinuationfrom the study.

Inclusion Criteria for Study Population:

-   -   Males and females of any ethnic group.    -   Ages≥18 and ≤55 years inclusive.    -   BMI within the range 18-32 kg/m² inclusive and within the weight        range 50-100 kg inclusive.    -   Females must be nonlactating, nonpregnant, and provide a        negative serum pregnancy test at screening and a negative urine        pregnancy test within 24 hours before receiving each dose of the        study drug. WOCBP must agree to use a hormonal contraceptive,        barrier contraceptive with additional spermicide, or an        intrauterine device. Female subjects who are postmenopausal must        have been postmenopausal for >1 year and have elevated serum FSH        consistent with postmenopausal status.    -   Generally of good health, evidenced by a lack of significantly        abnormal findings on medical history, physical examination,        clinical laboratory tests, vital signs, and ECGs.    -   Provide written informed consent. If HIPAA criteria are not        incorporated into the consent form, a separate addendum to the        informed consent form must be signed.    -   Willing and able to follow all rules of the protocol, including        returning for outpatient visits.

Exclusion Criteria for Study Population:

-   -   Any history of hypersensitivity to naloxone or related        compounds.    -   Subjects who meet American Academy of Pain Medicine, the        American Pain Society, and American Society of Addiction        Medicine criteria for addiction: “characterized by behaviors        that include one or more of the following: Impaired control over        drug use, compulsive use, continued use despite harm, and        craving,” but for this study not including tobacco dependence.    -   OOWSL4 score>4 within 1 hour prior to dosing.    -   History of or any current conditions that might interfere with        drug absorption, distribution, metabolism, and/or excretion.    -   Conditions of the nose that might interfere with intranasal drug        absorption, including any type of rhinitis, polyps, complete or        partial obstruction of any etiology (e.g., significant deviation        of nasal septum, recent trauma or surgery), active bleeding or        recent history of recurrent nose bleeds, or any ulcerations.    -   Any foreign object (including jewelry) in the nasal or oral        cavities or any perforation into either cavity or through the        septum or tongue (including piercings for jewelry).    -   Abnormal mucosa on nasal speculum examination including:        Atrophic mucosa, perforations, multiple polyps, fully obstructed        nasal passage on either side, hemangioma    -   Conditions of the mouth that might interfere with intraoral        (sublingual) drug absorption, including any type of ulceration,        infection, or recent trauma or surgery. Routine dental cleaning        within the previous two weeks or planned dental cleaning during        the study.    -   Poor oral hygiene, including gingivitis.    -   Abnormal oral mucosa on examination including:

atrophic mucosa, malignant or benign tumors (including fibromas andhemangiomas) or cysts, bullous lesions (eg, pemphigus or erythemamultiforme), glossitis, aphthous ulcers, lichen planus, leukoplakia,infections [bacterial, mycotic, viral (eg, herpetic)] Any use ofintranasal products (prescription, nonprescription, or anything elseadministered intranasally) within 4 weeks prior to dosing.

-   -   Use of any prescription drugs (except hormone replacement        therapy (HRT) for postmenopausal females, or contraceptive        medications) within 4 weeks prior to first dosing or during the        course of the study. Exceptions may be made on a case-by-case        basis for drugs with a short half-life (eg, tetracycline) and/or        no known significant drug interactions (eg, finasteride).    -   Use of any nonprescription medications, including vitamins and        herbal or mineral supplements, during the 7 days preceding or 2        days following any dosing. Exceptions may be made on a        case-by-case basis for medications with a short half-life.    -   Participation in a clinical drug study during the 30 days        preceding the initial dose in this study.    -   Any significant illness within 4 weeks prior to the first        dosing.    -   Donation of blood or blood products within 30 days prior to        study drug administration or anytime during the study.    -   Refusal to abstain from food at least 10 hours preceding and 4        hours following study drug administration or refusal to abstain        from caffeine- or xanthine-containing beverages entirely during        each confinement.    -   Alcohol intake exceeding the equivalent to >21 units/week (12 oz        beer=4 oz wine=1.5 oz shot=1 unit).    -   Consumption of alcoholic beverages within 48 hours of study drug        administration.    -   History of smoking within 45 days of study drug administration        (must have a negative urine cotinine at screening).    -   Positive results at screening of urine drug screen, blood        alcohol, or serology, including anti-HBc and anti-HCV.    -   the Investigator believes the subject to be unsuitable for some        reason not specifically stated in the exclusion criteria.

Method of Administration:

Subjects were administered the study medication on the mornings of eachdosing day. Subjects were dosed following an overnight fast of at least10 hours. After the dosing, subjects remained in an upright sittingposition for a minimum of 4 hours. The intranasal doses wereadministered via a metered dose nasal spray device. 200 μl per nostrilwere administered for a total volume of 400 μl. For each intranasaladministration, the head was tilted slightly forward. Subjects wereinstructed to refrain from blowing the nose or sneezing afteradministration. Subjects who receive intranasal dosing documented anysneezes that occurred within 5 minutes of dosing in the sourcedocuments.

The sublingual dose of naloxone was administered by having the subjectretain the solution (0.4 ml) under the tongue for 5 minutes, after whichthe mouth was thoroughly rinsed with water and the expectorated rinseresidue discarded. Subjects were in a standing or upright sittingposition. Subjects were instructed not to swallow any of the rinse. Theyalso refrained from drinking water for 1 hour after the rinse.Intravenous naloxone will be given as a 30-second bolus while thesubject is sitting.

Results:

Safety:

The incidence of treatment-emergent adverse events (TEAEs) was similaracross all treatment groups: 8 mg intranasal naloxone [3 TEAEs]; 16 mgintranasal naloxone [5 TEAEs]; 16 mg sublingual naloxone [1 TEAE]; 1 mgintravenous naloxone [4 TEAEs]. The most common TEAEs occurred in theGastrointestinal Disorders and Nervous System Disorder SOCs (SystemOrgan Class).

Gastrointestinal Disorders TEAEs were observed in the 16 mg intranasal,1 mg intravenous, and 16 mg sublingual groups only, whereas NervousSystem TEAEs were observed in the 8 mg and 16 mg intranasal and 1 mgintravenous groups only.

There were no deaths, serious adverse events, or other significantadverse events.

One subject recorded a markedly abnormal high triglyceride value (8.355mmol/l) on Day 44 of the study. However, the subject had recorded atriglyceride value above the normal range (4.189 mmol/l) on Day −9,prior to receiving study drug.

Another subject reported a markedly abnormal low potassium value (3.3mmol/l), a markedly abnormal high SGPT value (371 U/l), and a markedlyabnormal high total bilirubin value (39.33 umol/l) on Day 44 of thestudy. Potassium, SGPT, and total bilirubin values for this subject werenormal prior to the subject receiving study drug. These laboratoryfindings were observed during the routine lab evaluation and notreported as suspected adverse events by the investigator. Therefore, acausality assessment was not provided. Due to the timely relationship tothe administration of the investigated drug the sponsor rated the eventto be “possibly” related according to the WHO algorithm.

No clinically relevant changes in ECG occurred.

Three subjects had markedly abnormal changes in pulse rate and onesubject had a markedly abnormal change in blood pressure. TEAEs ofvasovagal attack were reported in 3 subjects after intranasalapplication of naloxone (2 subjects: one subject after 8 mg and onesubject after 16 mg) and intravenous bolus (1 mg) administration (1subject). No overall trend in abnormal vital sign changes was observedin this study.

Concomitant therapy was administered to 6 subjects for 10 TEAEs. Threeof these 10 TEAEs were vasovagal attacks and subjects were placed in thesupine position to recover. No additional medication was given to thesesubjects. One subject received additional medication for headache twice.Additional medication was administered for single events of hemorrhoidremoval, urticaria, gastroesophageal reflux, nausea and urinary tractinfection.

Pharmacokinetic:

Following intranasal administration of naloxone there was a very earlyappearance of the drug in the systemic circulation, with peak plasmaconcentrations being attained as early as 6 minutes (median 18 minutes)after dosing. Mean absolute bioavailabilities of 32% and 27% wererecorded from the 8 mg and 16 mg doses respectively, by dividing the AUCof the intranasal naloxone by the AUC of the intravenous referencenaloxone and multiplying by 100%. In contrast to the rapid eliminationhalf life associated with the intravenous reference (<1 h), mean halflives of several hours were recorded from the 8 mg and 16 mg intranasaldoses, respectively. These data indicate a substantial level ofabsorption of naloxone by the intranasal route coupled with a reasonablyslow elimination pattern. In contrast, the mean absolute bioavailabilityof naloxone when administered by the sublingual route was approximately2% versus the intravenous reference. This is comparable to that recordedpreviously following oral administration.

The mean pharmacokinetic parameters for naloxone are depicted in FIG. 2.

Example 2

Based on the data gained in Example 1, the following predictions ofamounts of naloxone administered intravenously or intranasally werecarried out.

A typical starting point for an intravenous administration of naloxoneis in the range of about 0.4 mg (IV). Based on the AUC-values for 1 mgIV naloxone, 8 mg IN naloxone and 16 mg IN of example 1, it can beestimated that the range of dose-proportionality to 1 mg IV is in therange of 3 mg to 4 mg for IN naloxone. For 0.4 mg IV naloxone, thisresults in typical starting amounts for naloxone administeredintranasally ranging from 1.2 mg to 1.6 mg.

Based on the original data of the study of example 1 on either 8 mgnaloxone or 16 mg naloxone administered intranasally (IN) and of 1 mgnaloxone administered intravenously (IV), plasma concentrations werepredicted for the following amounts: 0.4 mg naloxone IV, 1.2 mg naloxoneIN and 1.6 mg naloxone IN.

Using a first method (Excel), the Cmax and AUCt-values based on theoriginal data for the 8 mg naloxone administered IN and the 1 mgnaloxone IV were calculated by performing non-compartmental analysis onthe mean profiles which had been scaled to the proposed doses with thefollowing results:

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 1535.2 3159.6 1.6 mg IN 2046.94212.8 0.4 mg IV 4735.2 4578.9

The corresponding curves are depicted in FIG. 3 (for the total timeperiod of 36 h) and in FIG. 4 (for a time period of 4 h).

Using Excel, the Cmax and AUCt-values based on the original data for the16 mg naloxone administered IN and the 1 mg naloxone administered IVwere also calculated by performing non-compartmental analysis on themean profiles which had been scaled to the proposed doses with thefollowing results:

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 1052.5 2585.0 1.6 mg IN 1403.43446.7 0.4 mg IV 4735.2 4578.9

The corresponding curves are depicted in FIG. 5 (for the total timeperiod of 36 h) and in FIG. 6 (for a time period of 4 h).

Using a second method (WinNonlin Modeling), the original data for the 8mg naloxone administered IN were fitted by a compartmentalpharmacokinetic model followed by the simulations of the concentrationsbased on the model. The corresponding Cmax and AUCt-values are asfollows (for the total time period of 36 h):

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 1599.5 2876.2 1.6 mg IN 2132.63835.0

The corresponding curves are depicted in FIG. 7 for a time period of 4 htogether with the predicted concentrations using Excel (see above).

Using WinNonlin, the original data for the 16 mg naloxone administeredIN were also fitted by a compartmental pharmacokinetic model followed bythe simulations of the concentrations based on the model. Thecorresponding Cmax and AUCt-values are as follows (for the total timeperiod of 36 h):

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 893.5 2163.1 1.6 mg IN 1191.32884.1

The corresponding curves are depicted in FIG. 8 for a time period of 4 htogether with the predicted concentrations using Excel (see above).

As can particularly be derived from FIG. 7, the IN naloxone plasmalevels predicted for amounts of 1.2 mg and 1.6 mg, respectively, displaya smoother increase with a longer plateau compared to IV administrationof 0.4 mg. However, the initial slope of the IN-curves is rather steepas well. Further, the IN-curves display a rather smooth declinefollowing Cmax compared to the IV curve.

Example 3

As evident particularly from FIGS. 4, 6, 7 and 8, the plasmaconcentration curve predicted for an amount of 0.4 mg naloxone IVdisplays two peaks, wherein the first peak after a few minutes isfollowed by a second peak corresponding to the Cmax-peak.

Due to this rather unusual IV profile, it was decided to exclude oneoutlying subject who was apparently responsible for the “double peak IVprofile” when predicting the plasma concentration curve for an amount of0.4 mg naloxone administered intravenously. The calculations using Exceland WinNonlin for the 1.2 mg naloxone IN and 1.6 mg naloxone INcorrespond to the data as shown in Example 2.

Using Excel, the Cmax and AUCt-values based on the 1 mg naloxone IV dataexcluding the outlying subject were calculated by performingnon-compartmental analysis on the mean profiles which had been scaled tothe dose of 0.4 mg IV with the following results (depicted again withthe IN-values based on the 8 mg IN data):

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 1535.2 3159.6 1.6 mg IN 2046.94212.8 0.4 mg IV 2881.7 3812.2

The corresponding curves are depicted in FIG. 9 (for the total timeperiod of 36 h) and in FIG. 10 (for a time period of 4 h).

In the following table, the values calculated for Cmax and AUCt based onthe 1 mg naloxone IV data excluding the outlying subject are shown incomparison to the Cmax and AUCt-values calculated for 1.2 mg IN and 1.6mg IN based on the 16 mg IN data:

Cmax (pg/ml) AUCt (pg · h/ml) 1.2 mg IN 1052.5 2585.0 1.6 mg IN 1403.43446.7 0.4 mg IV 2881.7 3812.2

The corresponding curves are depicted in FIG. 11 (for the total timeperiod of 36 h) and in FIG. 12 (for a time period of 4 h).

As already described in example 2, the original data for the 8 mgnaloxone administered IN were also fitted by a compartmentalpharmacokinetic model followed by the simulations of the concentrationsbased on the model (WinNonlin Modeling). The corresponding curvestogether with the 0.4 mg IV curve excluding the outlying subject (basedon Excel) are depicted in FIG. 13 for a time period of 4 h. FIG. 14shows the corresponding curves for the modeling based on the 16 mgnaloxone IN data together with the 0.4 mg IV curve excluding theoutlying subject (based on Excel).

Finally, FIGS. 15 and 16 summarize the data of example 3 described abovefor a period of 4 h.

Particularly FIG. 15 shows that the IN naloxone plasma levels predictedfor amounts of 1.2 mg and 1.6 mg, respectively, display a smootherincrease with a considerably longer plateau compared to IVadministration of 0.4 mg. It is also evident that the IN-curves displaya smooth decline following Cmax compared to the IV curve.

The invention claimed is:
 1. A method of treating opioid overdosing orat least one symptom thereof, the method comprising intranasallyadministering a patient in need thereof 100 μl of an intranasalpharmaceutical dosage form comprising naloxone or a pharmaceuticallyacceptable salt thereof dissolved in an aqueous application fluid in afinal concentration equivalent to between 18 mg naloxone HCl per mlaqueous application fluid and 50 mg naloxone HCl per ml aqueousapplication fluid, wherein the dosage form has a pH of ≤5.5 and does notinclude a permeability enhancer.
 2. The method of claim 1, wherein thefinal concentration of the naloxone or pharmaceutically acceptable saltthereof is equivalent to between 20 mg naloxone HCl per ml aqueousapplication fluid and 60 mg naloxone HCl per ml application fluid. 3.The method of claim 1, wherein the final concentration of the naloxoneor pharmaceutically acceptable salt thereof is equivalent to between 30mg naloxone HCl per ml aqueous application fluid and 50 mg naloxone HClper ml application fluid.
 4. The method of claim 1, wherein the finalconcentration of the naloxone or pharmaceutically acceptable saltthereof is equivalent to 40 mg naloxone HCl per ml aqueous applicationfluid.
 5. The method of claim 1, wherein the aqueous application fluidis water or an aqueous saline solution.
 6. The method of claim 1,wherein the dosage form is provided in a single dosing unit or twodosing units, dependent on whether the dosage form is provided byadministration to one nostril or by administration to two nostrils. 7.The method of claim 1, wherein the dosage form is a nasal spray, a nasalmucoadhesive dosage form, or a mucosal atomizer device.
 8. The method ofclaim 1, wherein the naloxone or pharmaceutically acceptable saltthereof is the only pharmaceutically active compound in the dosage form.9. The method of claim 1, wherein the dosage form is co-administeredwith an intramuscular and/or intravenous dosage form comprising naloxoneor a pharmaceutically acceptable salt thereof.
 10. The method of claim7, wherein the dosage form is provided in a single dosing unit foradministration administered to one nostril.
 11. A method of treatingopioid overdosing, the method comprising intranasally administering apatient in need thereof 100 μl of an intranasal pharmaceutical dosageform comprising naloxone or a pharmaceutically acceptable salt thereofdissolved in an aqueous fluid in a final concentration equivalent to 20mg, 30 mg or 40 mg naloxone HCl per ml aqueous fluid and 50 mg naloxoneHCl per ml aqueous fluid, wherein the dosage form has a pH of ≤5.5 anddoes not include a permeability enhancer.
 12. A method of treatingopioid overdosing, the method comprising (i) intranasally administeringto one nostril of a patient in need thereof 100 μl of an intranasalpharmaceutical dosage form comprising naloxone or a pharmaceuticallyacceptable salt thereof dissolved in an aqueous fluid in a finalconcentration equivalent to 20 mg, 30 mg or 40 mg naloxone HCl per mlaqueous fluid and 50 mg naloxone HCl per ml aqueous fluid, wherein thedosage form has a pH of ≤5.5 and does not include a permeabilityenhancer and (ii) optionally repeating administration until an effectiveamount of naloxone is reached in the systemic circulation of the patientto counter the effect of the opioid.
 13. A method of treating opioidoverdosing, the method consisting essentially of (i) intranasallyadministering to one nostril of a patient in need thereof 100 μl of anintranasal pharmaceutical dosage form comprising naloxone or apharmaceutically acceptable salt thereof dissolved in an aqueous fluidin a final concentration equivalent to 20 mg, 30 mg or 40 mg naloxoneHCl per ml aqueous fluid and 50 mg naloxone HCl per ml aqueous fluid,wherein the dosage form has a pH of ≤5.5 and does not include apermeability enhancer and (ii) optionally repeating administration untilan effective amount of naloxone is reached in the systemic circulationof the patient to counter the effect of the opioid.